Submissions for variant NM_000251.3(MSH2):c.1662-18T>C

dbSNP: rs376235435

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076223	SCV000107247	uncertain significance	Lynch syndrome	2018-10-18	reviewed by expert panel	curation	Insufficient evidence
Counsyl	RCV000412305	SCV000489205	likely benign	Lynch syndrome 1	2016-09-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000442754	SCV000513660	likely benign	not specified	2017-12-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Diagnostics, LLC DBA Color Health	RCV000771185	SCV000903148	likely benign	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000442754	SCV001478776	likely benign	not specified	2021-01-11	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1662-18T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by published functional studies. The variant allele was found at a frequency of 2.8e-05 in 249272 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1662-18T>C in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One database (UMD) reports its presence in an individual with sporadic colorectal cancer (<50 years old) with mismatch repair function in tumor cells reported as "MSS / MLH1+MSH2+MSH6+" and an in-vitro RT-PCR analysis as normal splicing. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory ( MSH6 c.3261dupC , p.Phe1088LeufsX5), providing additional supporting evidence for a benign role. These findings do not support an actionable involvement of this variant in the etiology of disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=3; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae	RCV002055085	SCV002395024	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000771185	SCV002534391	likely benign	Hereditary cancer-predisposing syndrome	2021-03-14	criteria provided, single submitter	curation
Ambry Genetics	RCV000771185	SCV002706541	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.